Maternal use of certain substances, such as ethyl alcohol (ethanol), tobacco, caffeine and marijuana, may be toxic to the placenta as well as to the fetus. The resulting diminished placental function (decreased hormone production or deprivation of essential nutrients) could lead to intrauterine growth retardation (IUGR). Such placento-toxicity could occur regardless of the maternal nutritional status: selective fetal malnutrition. While each substance alone has the potential for placento-toxicity, humans frequently use more than one substance simultaneously, so that combined substance use may be even more detrimental. To test this hypothesis, we will be evaluating the in vitro effect of the major xenobiotics found in the aforementioned substances: ethanol (and its metabolite, acetaldehyde); nicotine and thiocyanate: caffeine; tetrahydrocannabinol. The effect of each xenobiotic (or combinations) upon critical placental function will be measured in vitro using human placental tissue: amino acid uptake and transport; folic acid transport; folic acid receptor activity; steroid hormone biotransformation; (Na,K)-ATPase activity. For this purpose, human placental slices, placental vesicles and isolated perfused human placentae will be utilized. In addition to human placentae, the aforementioned physiologic and biochemical parameters will be measured in rat placentae following in vivo xenobiotic exposure. This model permits variation in dosage and gestational timing, as well as correlation with gross teratogenic effects upon the rat fetus. Folic acid receptor and (Na,K)-ATPase activities will also be measured in primate placentae, exposed chronically (in vivo) to ethanol. Finally, after bypassing the placenta, xenobiotic effects upon fetal organ protein synthesis will be evaluated in rodents. The findings of this project will be of potential importance in the prevention of birth defects and possibly the determination of a margin of safety (if any) for substance use during pregnancy.